rs2499846

Positions:

• chr1-161963258-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007348.4(ATF6):​c.*4604G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.638 in 152,148 control chromosomes in the GnomAD database, including 32,346 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.64 (32346 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ATF6 NM_007348.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.217

Genes affected

ATF6 (HGNC:791): (activating transcription factor 6) This gene encodes a transcription factor that activates target genes for the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress. Although it is a transcription factor, this protein is unusual in that it is synthesized as a transmembrane protein that is embedded in the ER. It functions as an ER stress sensor/transducer, and following ER stress-induced proteolysis, it functions as a nuclear transcription factor via a cis-acting ER stress response element (ERSE) that is present in the promoters of genes encoding ER chaperones. This protein has been identified as a survival factor for quiescent but not proliferative squamous carcinoma cells. There have been conflicting reports about the association of polymorphisms in this gene with diabetes in different populations, but another polymorphism has been associated with increased plasma cholesterol levels. This gene is also thought to be a potential therapeutic target for cystic fibrosis. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATF6	NM_007348.4	c.*4604G>A		3_prime_UTR_variant	16/16	ENST00000367942.4	NP_031374.2
ATF6	NM_001410890.1	c.*4604G>A		3_prime_UTR_variant	16/16		NP_001397819.1
ATF6	XM_011509308.1	c.*4604G>A		3_prime_UTR_variant	16/16		XP_011507610.1
ATF6	XM_011509309.1	c.*4604G>A		3_prime_UTR_variant	16/16		XP_011507611.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATF6	ENST00000367942.4	c.*4604G>A		3_prime_UTR_variant	16/16	1	NM_007348.4	ENSP00000356919	A2
ATF6	ENST00000681738.1	c.*56+4548G>A		intron_variant, NMD_transcript_variant				ENSP00000505025
ATF6	ENST00000681801.1	c.*56+4548G>A		intron_variant, NMD_transcript_variant				ENSP00000505998

Frequencies

GnomAD3 genomes AF: 0.638 AC: 96994 AN: 152030 Hom.: 32332 Cov.: 33

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.614

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.519

Gnomad SAS AF: 0.588

Gnomad FIN AF: 0.816

Gnomad MID AF: 0.658

Gnomad NFE AF: 0.744

Gnomad OTH AF: 0.642

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.638 AC: 97042 AN: 152148 Hom.: 32346 Cov.: 33 AF XY: 0.636 AC XY: 47351 AN XY: 74396

Gnomad4 AFR AF: 0.471

Gnomad4 AMR AF: 0.536

Gnomad4 ASJ AF: 0.705

Gnomad4 EAS AF: 0.520

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.816

Gnomad4 NFE AF: 0.744

Gnomad4 OTH AF: 0.637

Alfa AF: 0.662 Hom.: 5794

Bravo AF: 0.609

Asia WGS AF: 0.518 AC: 1802 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.24
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2499846; hg19: chr1-161933048;